Enol ethers of 6-methyl-3-oxo-4, 6-dienic steroids



3,153,060 ENUIL ETHERS F 6-METH1L-3-GXO-4,6-

DIENKC STERGIDS George Cooley, Bernard Ellis, and Vladimir Petrow, London, England, assignors to The British Drug Houses Limited No Drawing. Filed 0st. 2, 1962, Ser. No. 227,706 Claims priority, application Great Britain, Get. 10, 1961,

9 Claims. (Cl. 260-3972) This invention is for improvements in or relating to organic compounds and has particular reference to a new class of enol ethers of 6-methyl 3-oxo-4,6-dienic steroids.

It is an object of the present invention to provide a new class of enol ethers having the general Formula 1 below which compounds are of value on account of their biological properties and as intermediates for the preparation of compounds having valuable biological properties.

The invention also provides the following specific new enol ethers:

17a-acetoxy-3-ethoxy-6-methylpregna-3,5,7-trien-20-one 17m acetoxy 3 cyolohexyloxy-6-methylpregna-3,5,7-

trien-ZO-one 17a \acetoxy 3 methoxy-6-methylpregna-3,5,=7-trien-20- one i which compounds are potent progestational agents when administered by the oral route,

The invention alsoprovides a process for the preparation of the enol ether-s (I) utilising as the starting materials the corresponding 6-methyl-3-oxo-4,6-dienic steroids having the general Formula 11 below.

According to the present invention there is provided a process for the preparation of enol ethers of the general Formula I' Me W 1 r Me (I) where R is an alkyl or alicyclic radical containing not more than 7 carbon atoms, which process comprises reacting a 6-methyl 3-oxo-4,6-dienic steroid havingthe general Formula II l (II) United States Patent 0 with an aliphatic or al-icyclic alcohol (containing up to 7 carbon atoms) or with an orthoformic es-ter thereof in the presence of a catalytic quantity of H ions.

The most convenient method comprises reacting the 6- methyl 3-oxo-4,-6-dienic steroid (II) with a trialkyl orthozformate HC(O.R) where R is a lower :alkyl group containing up to 7 carbon atoms in the presence of a catalytic quantityof the corresponding alcohol (ROI-I, where R has the same meaning as above) and an acid catalyst, in an inert solvent, when it is converted in high yield into the enol ether (1).

In a second method the desired enol ether may be dormed by reacting a o-methyl 3-oxo-4,6-dienic steroid (11) with methyl or ethyl orthoformate and thereafter reacting the resulting pie-formed enol methyl or ethyl ether with the desired alcohol (-for example cyclohexanol).

In carrying the process into eifect, the starting material (11) maybe dissolved in an anhydrous inert solvent which may be, for example, tetrahydrofuran, dioxan, benzene or toluene. The trialkyl-orthoformate, the corresponding alcohol, and the acid catalyst may be added in any order. The trialkyl orthoforrnate is present preferably in somewhat greater than. one molar proportion, but a large excess is not harmful. The quantity of the corresponding alcohol is not critical and may be conveniently :from 1% to 20% of the volume of the trialkyl orthoforrnate employed. The acid catalyst may be a strong acid such as sulphuric, toluene-p-sulphonic, perchloric or hydrochloric acid. The reaction wi-ll proceed at any temperature between 0 and 100 C., but is most conveniently performed at temperaturesbetween 50 and 100 C., when it is generally complete in from 1 hour to 24 hours.

The product may be isolated in any convenient manner. Thus when dioxan is employed as the solvent, the acid catalyst may be neutral-ised by the addition of excess of a base such as pyridine or triethylamine, and the solution diluted with water until the product separates out. It a solvent is used which is .not miscible with water, a base such as pyridine may be added, and the solution may then be Washed with water, dried over anhydrous sodium sulphate, and the solvent removed. The products may be purified by crystallisation from suitable solvents such as methanol or acetone/ hexane preferably with the addition of a drop of pyridine to ensure the stability of the enol ether system.

The process of the invention may be applied to '6-methyl 3-oxo-4,6-dienic derivatives ofcholestane, androstane,

pregnane and spirostane which may "contain additional unsaturated linkages at positions such as 9-11, 11-12, 15-16, 16-17, 17-20 and 20-21, p The following additional groups will not, in general, interfere withthe process of the invention:

Hydroxy or acyloxy groupsat positions such as C-ll,

' 16, 17, 20 and 21;

OX0 groups at positions such as 011, 17 and 20; Alkyl groups containingup to 4 carbon atoms, and in particular methyl groups, at positions such as C-1, 2, 11, 16,17 and 21; g Ethynyl groups and substituted ethynyl groups containmg up to 4 carbon atoms at position C-17;

Methylene groups at positions such as (3-11, 16 and 16-17; J

Halo groups, and in particular fluoroand chlorogroups at positions such as 0-9, 11, 16, 17 and 21;

Isopropylidenedioxy at position 1617 in 20-oxo pregnanes,and

Bis-methylenedioxy at position 17ci,20220,21.

Following is a description by way of example of meth Ode of carrying theinvention into effect. g Y r EXAMPLE 1 I 7 a-Alcetoxy -3-E thxy-6-M ethyl pregna-3,5 ,7- Trim-ZO-One 171x acetoxy 6 methylpregna 4,6 diene 3,20- dione (Ellis, Kirk, Petrow, Waterhouse and Williamson, J. Chem. Soc., 1960, 2828) (1.5 g.) in dry benzene (25 ml.) was treated with triethylorthoformate (1 ml.), ethanol (1 ml.) and toluene-p-sulphonic acid (10 mg), and the mixture heated under reflux for 3 hours. After cooling, pyridine (1 ml.) was added, the mixture washed twice with water, dried and the solvents evaporated in vacuo. The product was purified from ethanol containing a trace of pyridine to give 17a-acetoxy-3-ethoXy-6- methylpregna-3,5,7-trien-20-one as yellow needles, M.P. 195 to 200 C., [06150 127 (0., 0.887 in chloroform containing 0.2% pyridine), A 322.5 mu (6 19,060

713%? 1738, 1719, 1648 and 1616 omr EXAMPLE 2 Xy 6 methylandrosta 4,6 dien 3 one (Ellis, Kirk, Petrow, Waterhouse and Williamson, J.

Chem. Soc., 1960, 2828) (0.7 g.) in redistilled benzene 10 ml.) was treated with methyl orthoformate (0.4 ml.), methanol (0.4 ml.) and toluene-p-sulphonic acid (5 mg). The mixture was heated under reflux for 3 hours, cooled, and pyridine (0.5 ml.) added. After being washed with water, the mixture was dried over sodium sulphate, the solvents removed in vacuo, and the product triturated with methanol. Crystallisation from methanol containing a trace of pyridine gave 17fl-acetoxy-3-methoxy-6- methylandrosta-3,5,7-triene in prisms, M.P. 137 to 145 C., [11] 6()? (c., mu (6 12,000),

1737, 1661 and 1647 cm.-

EXAMPLE 3 Nuinl 'y 1625 and 1660 cm.

EXAMPLE 4 A solution of 6 methylcholesta-4,6-dien-3-one (Ellis, Kirk, Petrow, Waterhouse and Williamson, 1. Chem. Soc., 1960, 2828) 1.5 g.) and toluene-p-sulphonic acid (50 mg.) in dry'benzene ml.), methanol (1 ml.) and methyl orthoformate (1 ml.) was heated under reflux for 3 hours. The product was isolated as described in the foregoing examples to give 3-methoxy-6-methylcholesta-3,5,7-triene with 17oi-Acetoxy-3-Metlz0xy-6-Methylpregna-3,5,7 Trien-ZO-One 1 17a acetoxy 6 methylpregna '4 4,6 dien- 3,20-

1.05 in chloroform), h 320.5

EXAMPLE 6 1 7 a-A cet0xy-3-Cy|cl0hexyl0xy-6Methy lpregna- 3,5 ,7-Trien-20-One A solution of 17o1-acetoxy;3-methoxy-6-methylpregna- 3,5,7-trien-20-one (1.34 g.) (prepared as in Example 5) in dry benzene (150 ml.) and cyclohexanol (3 ml.) was distilled until 60 ml. of distillate had been collected. Toluene-p-sulphonic acid (6 mg.) was then added and distillation continued over a period of 3 hours when most of the solvents had been removed. Pyridine (3 drops) was then added and residual solvents removed under high vacuum. The dark brown residue was purified from methanol to give 17a-acet0xy-3-cyclohexyloxy-6-methylpregna-3,5,7-trien-20-one as pale yellow needles, M.P. 200 to 207 C., [11],; -102 (c., 0.86 in CHCl containing 2% of pyridine), A 324 mu (6 20,440).

EXAMPLE 7 6-methyla11drosta-4,6-diene-3,17-dione (Ellis, Kirk, Pet- 7 row, Waterhouse and Williamson, J. Chem. Soc., 1960,

2828) (6 g.) in sodium-dried benzene (100 ml.) was treated with triethylorthoformate (4 ml.), ethanol (4 ml.)

7,233 1743, 164.9 and 1618 0111.!

EXAMPLE 8- 17a acetoxy 6 methyl 16 methylenepregna 4,6- diene-3,20-dione (British Patent No. 886,619) (10 g.) in dry benzenev (165 ml.) was treated with triethylorthoformate (6.5 ml.), ethanol (6.5 ml.) and toluene-p-sulphonic acid (330 mg). The mixture was heated under reflux for 2 hours, cooled, and pyridine (6.5 ml.) added. After being washed with Water, the mixture was dried, the solvents removed in vacuo, and the residue purified from ethanol containing a trace of pyridine. 17a-acetoxy- 3 ethoxy 6 methyl 16 methylenepregna 3,5,7- trien-20-one separated in prisms, M.P. 194 to 198 C., [a] 18S (c., 1.0 in chloroform containing 0.2% pyridine), h 324 mu (e 18,810),

1746, 1720, 1710, 164.9 and 1615 emf max.

EXAMPLE 9 17a1- acetoxy 6,1611 dimethyl 3 ethoxypregna-3,5,7-

dione (3.0 g.) in dry benzene (50 ml.) was treated with trimethyl orthoformate (2 ml.), methanol (2 ml.) and toluene-p-sulphonicacid (100 mg), and the mixture heated under reflux for 3 hours. After cooling, pyridine (2 ml.) was added, the mixture washedtwice with water (50ml), dried and the solvents evaporated in vacuo.- The product-was purified from methanol containing a trace of pyridine to give 17o1-acet0xy-3-methoxy-6-1nethy1- trieu-20-one separated in plates, M.P. 202 to 207 C., [oc] -84 (c., 1.0 in' chloroform containing 0.2% pyridine), A 323 mu (e 19,670),

vggg 1744, 1716, 1657 and 1618 cmr We claim:

1. A 6- methyl-3,5,7-trienic steroid havingat the 17 position a Side chain selected from the group consisting of those characterising cholestane, androstane, pregnane and spirostane compounds and having an -OR group attached to the number 3 carbon atom, wherein R is a radical selected from the group consisting of alkyl and alicyclic containing not more than 7 carbon atoms.

2. 17a acetoxy 3 ethoxy 6 methylpregna 3,5,7- trien-20-one.

3. 17a acetoxy 3 cyclohexyloxy 6 rnethylpregna- 3,5,7-trien-20-one.

4. 17oz acetoxy 3 methoxy 6 methylpregna-3,5,7- trien-ZO-one.

5. 1713 acetoxy 3 methoxy-6-methylandrosta 3,5,7- triene.

6. 3-methoxy-6-methylcholestat-3,S,7-triene.

5 3,5,7-trien-2 O-one.

References Cited in the file of this patent UNITED STATES PATENTS Dauben et a1. Feb. 23, 1960 OTHER REFERENCES Fieser et al.: Natural Products Related to Phenanthrene, 3rd Ed., 1949, pp. 371-372, Reinhold Publishing Corp., 430 Park Avenue, New York 22, N Y. 

1. A 6-METHYL-3,5,7-TRIENIC STEROID HAVING AT THE 17 POSITION A SIDE CHAIN SELECTED FROM THE GROUP CONSISTING OF THOSE CHARACTERISING CHOLESTANE, ANDROSTANE, PREGNANE AND SPIROSTANE COMPOUNDS AND HAVING AN -OR GROUP ATTACHED TO THE NUMBER 3 CARBON ATOM, WHEREIN R IS A RADICAL SELECTED FROM THE GROUP CONSISTING OF ALKYL AND RADICAL SELECTED FROM THE GROUP CONSISTING OF ALKYL AND ALICYCLIC CONTAINING NOT MORE THAN 7 CARBON ATOMS.
 6. 3-METHOXY-6-METHYLCHOLESTA-3,5,7-TRIENE. 